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Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed (1989)

Chapter: ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS

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Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 81
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 82
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 83
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 84
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 85
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 86
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 87
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 88
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 89
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 90
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 91
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 92
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 93
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 94
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 95
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 96
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
×
Page 97
Suggested Citation:"ANTIMICROBIAL RESISTANCE IN HUMANS AND ANIMALS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 98

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80 TABLE V- 1 RESISTANCE TO ANTIMICROBIAL AGENTS IN SALMONELLA ISOLATES ( 19 7 9 - 19 8 0 ) II). (S) IIOUTfS USISTMT TO: .,_ (10 tetro· wlfon­ ... . ISCIUTfl qcl iM ••• c f l l fn .... 141 ( s ) 19 ( tJ ) 0 ( 0 ) 26 ( 11 ) 6 ( 4 ) 4 ( J ) J4 ( 24 ) -�� Z4 ( t ) 6 C ZS ) O C 0 ) 6 ( zs ) 1 ( ·4 ) 0 ( 0 ) 9 (J7.S ) block ley ss ( 2 ) 0 ( 0 ) 0 ( 0 ) s ( 9 ) 0 ( 0 ) J ( s ) 7 ( 1J ) .... enter f t ldla 114 (Jt ) 15 ( 2 > o c 0 ) 12 ( 1 ) 2 ( 0 ) 12 ( 1 ) a c J , (A) ... . . u..... 121 ( 4 ) 20 ( 17 ) 2 ( 2 ) SJ C 44 ) • ( 21 ) a c D , .. ( S6 ) lnfent l a 127 ( 4 ) J c 2 > o c O > 12 ( 9 ) 2 ( 2 ) 0 ( 0 ) tJ ( to ) (MIS. .ntevldeo 61 ( 2 ) 6 ( 10 ) 0 ( 0 ) 2 ( J ) 2 ( J ) 0 ( 0 ) I ( 1J ) STAff .......-c 14 ( J ) I ( 10 ) 4 ( s ) 10 ( 12 ) I ( 10 ) 7 ( I ) 10 ( 12 ) uaATOIT) orwtl...,. J4 ( t ) z c 6 ) 0 ( 0 ) 0 ( 0 ) 0 ( 0 ) 0 ( 0 ) 2 ( 6 ) lt • ...,, 7S ( J ) 17 ( ZJ ) J ( 4 ) 15 ( 20 ) I ( 11 ) 14 ( 19 ) zz c 29 ) t)'llll f -· � 9S9 CJ4 ) 1 19 ( 12 ) J ( 0 ) 1J4 ( 14 ) 16 ( 9 ) 52 ( s ) 111 ( 20 ) • v.copen. 261 ( 9 ) JZ C ,� ) t c 0 ) 41 ( 16 ) ZJ ( • ) ZJ ( ' ) 41 ( ,. , 247 C 1 . 7 ) 1J CO.S ) J16 ( 1 1 . 2 > 164 C S .l ) tO C S. t ) U7 ( 15 . 5 ) .... 197 (11 ) sz c 26 ) JO ( ts ) 67 ( J4 ) 4J ( 22 ) 31 ( 19 ) 19 ( 40 ) -�� 167 ( 10 ) 11 ( 49 ) 2 ( 1 ) 102 ( 61 ) 19 ( 47 ) 9 ( s ) tJO ( 71 > MiliA&. blocli: l ey J6 ( 2 ) 0 ( 0 ) 0 ( 0 ) 10 c a > 0 ( 0 ) 1 ( J ) 9 ( zs ) (I) -erltldla ss ( J ) 1 ( 2 ) 0 ( 0 ) 2 ( 4 ) 1 ( 2 ) 1 ( 2 ) 2 ( 4 ) ... . . , ...... 2'0 (14 ) 110 ( 46 ) 0 ( 0 ) 171( " ) 110 ( 46 ) 40 ( 17 ) 111 ( . , CIATICIIAL lnfont l a 61 ( 4 ) 15 C ZZ > J C 4 ) Z4 ( JS ) ' ( 1J ) s ( 7 ) 29 ( 0 ) WTII I IIAIT ....,.., .• S6 ( J ) s c 9 ) 0 ( 0 ) 19 ( J4 ) 15 ( 27 ) 12 ( 21 ) 21 CJ7.S > uaATOIT) .......-c 45 ( J ) I C 11 ) 1 C 2 ) 1J (29 ) 10 ( Z2 ) 10 ( Z2 ) 14 ( Jt ) oronl...,. 42 ( 2 ) o c 0 ) 0 ( 0 ) 7( 17 ) 2 ( s ) 2 ( s ) 7 ( 17 ) at • ...,, tJt ( I ) 14 ( 64 ) z c 2 ) 49 ( 37 ) 16 ( 66 ) 7 ( s ) •• c az > t)'llll l -·� S02 (29 ) J4S C 69 ) JZ C 6 ) m e n > . m e , , Z4J ( 41 ) , , 71 ) • v. coplft. 206 (12 ) 10 ( 69 ) 1 ( 0 ) 151 ( 77 ) 142 ( 69 ) 1 .. ( 52 ) 162 ( 19 ) 1 745 *' c41.4 , n C4 . 1 , 916 cS6.s , m c 44 .z , 476 cz7.J > t tJS ( " ) onmt SOOTYPfS c:llo ler-la 290 (41 ) 37 ( 1J ) 1 ( 0 ) 289 ( 100 ) 285 ( . , J7 ( 1J ) Zl9 ( 100 ) II MIIW.S derby 9S ( tJ ) 22 ( ZJ ) 2 ( 2 ) J1 ( JJ ) 16 ( 17 ) 6 ( 6 ) 40 ( 42 ) (C) cUil ln tZS ( 11 ) 1 00 ( • ) J ( 2 ) 106 C IS > 25 ( 20 ) 9S ( 74 ) 1 16 ( 9S ) (lAT. WTEIIIIAIT pul l - 95 Ctl ) 12 ( 1J ) 0 ( 0 ) 56 ( 59 ) I ( I ) 11 ( 12 ) 60 ( 6J ) uaATOIT) son dl-.ct 106 ( 15 ) 6J ( 59 ) 0 ( 0 ) 69 ( 65 ) 42 ( 40 ) 15 c 14 ) 19 ( 75 ) n1 2J4 cR.9 > 6 co.1 > ss1 c77.s > J76 csz.9 > 162 czz.1 > 514 ( 19 ) M TOTAL 2456 1071 (4J .9 ) 77 (J. 1 ) 15J7 (62.6 ) 1 141 (46.7 ) 631 (26.0 ) 1697 ( 69 ) s ource : Adapted from data compiled by the committee .

81 human or an animal to any speci fic antibiotic , nor to the dosage , nor to the route of administrat ion ( oral or parenteral ) . This could result in errors in j udgement , e . g . , the inabi l ity to d i fferent iate bacterial res istance to an antibiotic administered either parenterally or via the feed ( per os ) . ( Note : Penici l l in/ampicil l in is used as terminology to include pen ici l l in G to reflect the fact that , although this is the form of the P - l actam administered parenteral ly to l ivestock , susceptib i l ity test ing of salmonel l ae isolates from humans is performed with amp i c i l l in as the P - lactam drug . ) The prevalence of several serotypes can be seen to d i f fer greatly between the human and animal isol ate col l ections ( See Table V- 1 ) . Stra ins of � enteritidis constitutes 3 1 % o f human but only 3% of animal isol ates ; � chol eraesuis , � derby , � dubl in , � pul l orum , and § . san diego were found mostly in the animal isolate col l ection . OVeral l , res istance to each of the ant ibacterial agents tested or to any of the agents was more frequent in the animal than in the human col lect ions . Res istance was a l so disproport ionately prevalent in isolates of several serotypes ( e . g . , � typhimurium , � heidelberg , � anatqm , � agona , and � st . paul ) in both animal and human isolates . The frequency of res istance to the di fferent ant ibacterial agents had the same rank order of res istance in both anima l and human isolates as fol l ows : ( streptomycin>tetracycl ine>sul fonamide>ampic i l l in> chloramphenicol ) . Table V-2 arranges animal isolate data s imilar to that in Table V- 1 by serotype and ant ibiotype . Each ant ibiotype that was found in 2 % or more of the isolates of any serotype is shown in Table V-2 . The table shows that much of the res istance in the isolates of a given serotype is clustered into a sma l l number of ant ibiotypes , and that these preval ent ant ibiotypes vary greatly from serotype to serotype . When col lect ions of isolates representing several of the prevalent serotype-antibiotype combinations were tested ( e . g . , the ant ibiotype TSKUHA for � typhimurium var . copenhagen ) it was found that res istance in many of the isolates was due to a common resistance plasmid which they shared , even when the isolates came from different states or from both anima l s and humans . 15 The results shown in Table V-2 also i l lustrate a problem encountered in surveys of the prevalence of res istance in Salmone l l a spp . The res istance tends t o b e discont inuous , that is , clustered in groupings of multiple res istance in particular serotypes . Any survey that includes , for unsuspected ep idemiologic reasons , a disproportionate number of isolates belonging to one of these clusters wi l l not

82 TABLE V-2 PERCENTAGES + OF ANIMAL ISOLATES OF EACH COMMON SEROTYPE OF SALMONELLA THAT TESTED RES I STANT TO VARIOUS COMBINATIONS OF ANTIMICROBIAL AGENTS ANT I B IO- SEROTYPE .;. � TYPE* • - ! c c ... 0 ... 0 .2: ..: .. ... ... 0 ::> -:: .. - ... ::> - .. .. ... ... A c: 3 ... ... A • .. .. c "' ... ... :.. 0 ... c: :> ::> "' A - - • - ;; ;:: .. .. .., :;: .. .. • ... c; " c - .. c c c: .! "' -:: ... c ! .. ... .. :;: .. .. 8. c -0 .. c c: c: .g .. A ... 0 ::: . " ... .. � .. I! .... ... ... c 1: :a E :! .. u .. ... .. " .. ... c: c: 0 ..; ..r: c: c: '; ... & 0 '; ... - � .. 0 .., I ... .. � .., • • � � ... ... ... c: c: - � ..9 � .. w .. c: ... .!: .. ... .. :a a .. u 0 .. .; .. u ... c c ... .. .. "" .... .. "' ., "' .. .. ... "' "' Tts.:UHAGX 11 14 96 72 19 52 86 57 - 62 64 - 7& -34 - 4Cl. 1 7 - ZZ 4l JZ. ...zl_ J a 4l 2 � g 14 �� �� § 4 n 17 l!i § 12 3 20 - 28 26 11 15 12 24 20 26 14 12 12 40 u 13 17 17 18 13 15 22 26 21 28 13 •a 28 16 2 82 232 43 59 3e 473 1 1 1 1 58 35 76 29 3 3 7 1 1 2 29 47 74 67 5 9 1 25 5 7 1 67 1 34 78 29 71 7 287 33 *AGENTS TO WH I CH RES YSTANT T • tetra cycl i ne K • kanamyc i n A • amp i c i l l i n C • c h l o ramph e n i col U • s u l fo nam i d e s G • gentami c i n S • s tre ptomyc i n H • ceph a l o th i n X � s u l fa tr i me t ho pr i m + P e r c e n t a g e s l e s s t h a n 2 n o t s h own S ource : Adapted from O ' Brien e t a1 . IS - - - - - -

83 accurately represent the preval ence that might be found i n a larger or more broadly-based sample . Table V- 3 summa ri z es in chronologie order the prevalence of res istance in col l ections of salmone l l a isolates from humans and from animals in the United States . Among the human isolates , the first two reports , from the late 1 9 6 0s show s imilar preval ence of res istant stra ins at 2 1-2 2 t . 2 0 , � 9 Four reports o f studies done in the 1 9 7 0 s were based on reference laboratory col l ect ions--those of Cherubin et al . , 5 S aad and Farrar , l 9 O ' Brien et a1 . , 1 6 and MacDonald et a1 . 14 --the results in these surveys were in close agreement ; percentage of res istant stra ins ranged from 1 5 . 5 to 17 . 4 . The higher percentage reported during this period was the survey of Bissett et al . , 2 that showed 3 l t res istant stra ins . The report of Lorian , l 3 covering the decade from 1 9 7 5 through 1 9 8 4 , was produced by a d i f ferent method o f survei l lance than those mentioned above . This method was not based on col l ect ions of reference l aboratories , but on analys is of computer-data files from several hundred hospital l aboratories . Although these computer files did not give serotype ident i fication , there was broad geographic representation in this very large data file . Lorian ' s analys is of these data did not attempt to determine the percentage of isolates res istance to at least one of the tested antibacterial agents . However , we can proj ect that the percentage of isol ates res istant to any of the agents would be around J O t , s ince the res istance to either tetracycl ine or to ampici l l in alone was 2 2 t and 1 S t , respect ively , assuming a distribut ion of group ings of res istance s imilar to that seen in the other studies . Thus , we are left with the puz z l e of why these hosp ital -based survey data showed approximately twice the percentage res istance as the reference-laboratory-based surveys o f approximately the same time period . One pos s ible explanation is that the different report ing method for the data in the Lorian survey l 3 might have accounted for some of the observed dif ference in prevalence of res istance . These data did not include the primary measurements of the extent of res istance ( inhibition zone diameter or MIC ) , but only reported suscept ibil ity rather than res istance , and th is has been proj ected here to make the results comparable with those of the other studies . In Lorian ' s method the percentages in the intermediate range , which are not reported here , were reported as res istant , wh ile in the other studies , they would have been reported as nonres istant . The intermediate percentages for the ant ibacterial agents reported in the other studies , are too sma l l to account for the d i f ference between them and the Lorian data , a l so there was no informat ion on qual ity control

TABLE V- 3 RES ISTANCE TO ANTIMICROBIAL AGENTS AMONG ISOLATES OF SALMONELLAE FROM HUMANS AND ANIMALS IN THE UNITED STATES PERCENT RES I STANT TO NO . tetra - chl ora.- atrepto- sul fon - HOST PER I OD REG I ON I SOLATES cycl t ne phent col 11yct n mt de cm•- tn any I NVES T I GA T OR - -- -- -- - - - - -- - ---- ----·---- - - ------- -- --- - ------ -- - - - - -- - --- - - - - - - - ---- - -- - - - - - - - - -- - - - - - - - - - - - - 2D HtJ4AH " 1 967 NAT I ONAL 400 12 . 5 0 14 . 2 8 22 . 2 SCHROEDER ET A � " 1968 - 1969 NORTHEAST 292 8.2 0 15 11.5 13 . 5 21 . 6 W I NSHELL ET A� " 1970 NORTHEAST 315 11 . 7 0 14 . 9 9.5 17 . 4 CHERUB I M ET Al 5 1 9 7 1 - 1972 CAL I FORN IA 2246 20 . 3 1.5 26 19 . 5 18 . 5 31 B I SSET T E T AL l 19 " " 1 973 - 1974 GA AND SC 305 10 0.3 11 6 8 16 SAAO AND fARRAR " 1 9 7 5 - 1984 NAT I ONAl 20708 22 4 18 ?30 LOR I AN 13 1979 - 1 980 � " MA 2826 8.7 0.4 11 .2 5.8 5. 1 15. 5 O ' BR I EN ET AL � 1 9 79 - 1 980 NAT I ONAl 51 1 8.6 0.8 12 8 8 16 MACDONALD ET AL •• •• •• " 1 984 - 1 985 NAT I ONAl 485 13 2 12 . 2 1 9 24 - - - - - - - -- - - - - - - - - ----- - -- - - - - - - - - - --- - - -- - - - - - - -- - -- - - - - - - � TOTAl 28088 AN I MAl •• 1973 - 1974 GA AND SC 1 52 10 0 16 4 4 21 . SAAD AND fARRAR 19 " 1 9 7 9 - 1980 NAT I ONAl 2456 43 . 8 3.1 62 . 5 46 . 7 25 . 9 69 . 09 O ' BR I EN E T A L � 1 980 - 1981 NAT I ONAl 3 500 45 12 66 57 31 80 BlACKBURN E T AL 3 BOV " N E I 1 981 - 1 987 S . DAKOTA 207 80 62 PERSONAL COHH U N I CAT I ON " 1 985 - 1 986 TEXAS 621 47 39 fROM VET E R I NARY 1981 - 1987 S . DAKOTA 596 81 42 LABORATO R I ES PORC I N E " 1 985 - 1 986 TEXAS .51 37 23 ( COL E . T HAY E R . 1 986 - 1 987 . GEORG IA 223 69 72 l l BAL , WH I T fORO ) .. .. .. POULTRY 1981 - 1 987 S . DAKOTA 1 24 43 15 -- ---- - -- ---- - -- - - - -- - -- - - - - - - -- - - - - - - - -- ------ -- - --- - - - - - TOTAL 7930 Source : Adapted by the committee from data b Blackburn et a l . 3 , Bissett et a l . 2 Cherubin et a l . s Lorian l 3 , MacDona ld et al . l i , O ' Brien et a1 . 1 6 , Saad and Farrar 1 9 , Schroeder et a l . � o , Winshe l l et a l . 2 9 , and personal commun icat ions ( Cole , Libal , Thayer and Whit ford , Veterinary Laboratories ) .

85 i n the hundreds o f laboratories that generated the data reported in Lorian • s large survey . 13 The survey results reported by MacDonald et al . 14 showed a rise from 1 6 to 2 4 % from 1 9 8 0 to 1 9 8 5 for human isolates of salmonel l ae res istant to any of the tested ant imicrobial agents . These percentages are important , because they indicate that the antibacterial res istance found in human isolates of salmonellae has increased . Accordingly , the l atter value ( - 2 4 % ) would be the more nearly contemporary percentage to use in the risk assessment model . The val idity of the results of the 1 9 8 5 survey by MacDonald et al . 1 4 is supported by the geographic representation incorporated in its des ign and by its comparabil ity to the survey performed 5 years earl ier . Also , the percentage of res istance ( 1 6 % ) found in the earl ier ( 19 8 0 ) survey reported by MacDonald agrees cl osely with the percentages ment ioned in the three other surveys of that time period . Given the compl exity of the probl em , however , a sample of 4 8 5 isolates is not large . This i l lustrates the committee ' s earl ier concern about the inadequacy of surve i l l ance of res istance in isolates of salmonel l ae in the United states 1 when we cons ider that the 4 8 5 isol ates on which this survey was based were from nearly 2 0 0 , 0 0 0 human isolates of salmone l l ae serotyped by re ference l aboratories in the United States s ince the earl ier survey . The report by Saad and Farrar 19 of the percentage of res istant salmonel lae in animal isolates from Georgia and South Carol ina during 197 3 and 1 9 7 4 shows a rel atively l ow percentage of res istance , in contrast with the two l ater studies of animal isolates ( Table V-3 ) . This probably is due to regional dif ferences and sma l l - s i z ed samples , and thus does not represent a true national secular trend . Studies by O ' Brien et al . 1 6 covering the period 1 9 7 9 - 19 8 0 and by Blackburn et al . 3 covering 1 9 8 0 - 1 9 8 1--were both based on the same data source , namely , the large col l ection of an imal isolates at the National Veterinary Laborato� in Ames , I owa . Although the results of the Blackburn et al . 3 study showed somewhat higher percentage of res istance than the O ' Brien study , more recent data would be needed to determine whether these results represents a trend . In addition to these three surveys , veterinary laboratories in several states have provided results of susceptibil ity tests done on salmonel lae isolated in recent years . Yearly values for percentages of res istance showed no clear trends over time , so values for a l l years were averaged for each state and host spec ies , as shown in the l owest s ix l ines of Table V- 3 . Table V- 3 essentially ampl i f ies the observat ions o f Table V- 1 . The percentage o f isolates res istant to any ant ibacterial agent for which data are ava ilable in any of the nine col l ections of animal- isolates , except for the sma l l group reported by Saad e t al . , exceeds the percentage

86 reported i n any of the human isolate col l ections . The percentages reported for resistance to tetracycl ine are greater than those res istant to ampici l l in in eight of the nine col lections of human isolates and in a l l nine col l ections of animal isolates . The average percentage o f res istance of salmonellae isolates t o ampicil l in o r to tetracycl i ne in the animal col lections is 3 to 4 t imes greater than in the human col l ections . fREQUENCY OF PRUG BESISTAHCE IN CLINICAL IS OLATES OF E . COLI fROM HUMANS AND ANIMALS IN THE UNITED STATES The data in Table V-4 shows the percentages of isolates res istant to antimicrobial agents in collections of isolates of � £Qli from humans and animals in the United States . The data in the first row , reported by O ' Brien , is from a l l isolates tested during 1 9 8 6 by the laboratory of a l arge general hospital in Boston ( O ' Brien , 1 9 8 8 , personal commun ication ) . It is the committee ' s bel ie f that these percentages are s imilar to those commonly found in Un ited States hospital laboratories , because they are comparabl e to the percentages in the second row reported by Atkinson and Lorian from isolates tested over a decade in several hundreds hospitals in the United States . 1 The percentages in the l atter large study by Atkinson might be sl ightly inflated in comparison with the percentages in other col l ections , because they were reported as " percent nonsusceptibl e " --that is the total of res istant isolates plus isolates in the intermediate res istant category . The data in the first two rows of Table V-4 , reported by O ' Brien , Atkinson , and Lorian , are representative of data that are commonly reported by hospital laboratories . Data from this source are cons idered biased , because most of the isolates are from patients who are hospital i z ed presumably due to an i l lness , thus constituting a smal l group having more isolates that are res istant than the human population at l arge . The � £Qli isolates in the third row reported by Lester et al . from the general human population probabl e give a better representation of the res istance pro f i l e from the human population at large . These data are from a col lection of 10 random colonies of � QQli from stool cultures from each o f 3 8 healthy children who had not been treated with any antimicrobial agents for at l east 4 months be fore culture . The percentages of res istance reported in these community­ based isolates of � col i are about one-third o f those reported for hospita l - l aboratory isolates . The l ower part o f Table V-4 shows percentages of res istant isolates in various col lections o f animal isolates of � £Q!i . The first three rows are from earl ier studies by

TABLE V-4 RES ISTANCE TO ANTIMICROBIALS AMONG I SOLATES OF E . COLI FROM HUMANS AND ANIMALS IN THE UNITED STATES X R E S I STANT T O : . . . . . • . . . . . . . . . NO . OF t et r a • ch l or111 • a t repto• aul fon· �· · HOST SOURCE PER I OO REG I ON I SOLATES cyc l f ne phenf col lftYC f n lll f de cf l l fn I NVEST I GATOR • . • . . . . . • . . • . . • . • • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . 6 HUMAN HOSP I TAL 1 986 BOSTON 3757 26 8 27 29 O ' BR I EN . ET AL 1 .. " " 1 971 · 1 982 u.s • 1 . 8 mil 28 5 29 28 ATK I N SON NG LCRIM1 " COMMUN I T Y 1 985 BOSTON 388 12 1 9 10 LEST�R ET AL 12 AN I MAL PORC I NE 1 974 I LL I NOI S 530 90 1 .7 93 83 53 S I EGAL ET AL 21 0) ...,J " BOV I NE 1 974 . " 1 06 49 0 50 29 13 " " " " " n 1 974 MONTANA 431 0 2 1 1 1 " " " .. AN I MAL 1 980 u.s• 1 00 80 6 n 70 29 O ' BR I EN ET AL 15 .. BOV I NE 1 981 • 1 987 SOUT H DAKOTA 366 76 69 38 PERSONAL COMMUN I CAT I ON " II II 1 985 · 1 986 TEXAS 405 71 49 ' FROM VETER I NARY II II II 1 986 · 1 987 GEORG I A 265 57 55 35 LABORATOR I E S .. POR C I NE 1 98 1 · 1 987 SOUT H DAKOTA 1015 96 93 44 ( COLE , T HAYER , II II II 1 985 · 1 986 T EXAS 1 07 93 77 L I BAL , \JH I T FORO ) II II II 1 986 · 1 987 GEORG I A 405 93 62 .. II " II POUL T R Y 1 981 · 1 987 SOUTH DAKOTA ·30 83 80 31 " " " Source : Adapted b the committee from data by Atkinson and Lorian 1 , Lester et a1 . 12 , l O ' Brien et al . l S , l , S ieqal et a1 . 2 1 , and persona l communications ( Col e , Libal , Thayer and Whit ford , Veter inary Laboratories ) .

88 S iegal et al . of � � i n fecal samples from p igs and cattle on farms in I l l inois and from range cattle in Montana . 2 1 The isolates from range cattle were remarkable , in that scarce ly any of them were res istant to any o f the ant imicrobial agents tested . I solates from anima l hosts reported in the fourth row o f Table V-4 shows the res istance i n 1 0 0 � QQli stra ins chosen randomly from among the large col l ect ion of animal isol ates sent to the National Veterinary Re ference Laboratory for serotyp ing . The data in the other seven rows show the percentage res istance in the col l ections o f � � isolates from di f ferent animal host spec ies tested by the same veterinary l aboratories that provided the data on salmonel lae isol ates in Table V- 3 . In a l l col l ect ions of � QQli isolates res istance to tetracycl ine was more frequent than res i stance to ampicil l in , with the exception of those from range cattl e . In addit ion to the data in Table V-4 , data from other studies provide information about the res istance to antibacterials in salmone l l ae and � � i sol ated from anima l s in the United States . Fagerberg and her assoc i ates 6 surveyed fecal samples from product ion cattle , bro i l ers , and swine at var ious slaughter plants in the United States . Salmone l l ae were isolated from 5% of the bro i l ers , 5 % o f the production swine , 9 % o f the beef units , and 6 0 % o f the swine at the slaughter pl ants . The resulting 1 9 9 salmone l l a isol ates were of 2 7 serotypes ; 8 2 % of the stra ins were drug res istant . The survey results showed 1 , 5 6 3 stra ins o f � £Qli , o f which 9 5 % were drug-res istant : 7 2 % res istant to tetracycl ine , 6 0 % res istant to streptomycin , 8 4 % res i stant to sul fadia z ine , and 1 3 % res istant to amp ic i l l in . Gusta fson et al . 7 found d i f fering rates ( 1 0 to 8 4 % ) for the isolation of Salmonella from healthy market hogs taken at sl aughter plants in Pennsylvani a , Iowa and Georgia and d i f ferent percentages ( 0 -2 4 % ) of drug res istance among the isolates , although only 2 4 isolates out of 1 4 9 1 from 6 5 8 swine were res istant t o multiple ant ibacterials . A study by Spgaard 2 2 involved pigs without cl inical s igns of i l lness which had not been fed any ant ib iot ics in the ir feed but were given therapeutic dosages of ant ib iotics . A preval ence o f 7 4 % resistance was reported to one or more antib iotics . The incidence of res istance to sul fonamides , tetracycl ines , and streptomycin was high . Most stra ins were suscept ible to ampic i l l in and chloramphen icol . Pigs never given ant ibiotics either subtherapeut ically or therapeut ical ly showed a prevalence of res istance among � col i o f 5 3 % . Thus , the therapeutic use o f ant ibiot ics in swine accounted for an absolute 2 1% increase ( from 5 3 % to 7 4 % ) of organ isms res istance to various ant ibiotics . Langlois et a1 . 1 0 found tetracycl ine res istance in 7 6 % o f the fecal col i form organ isms in swine fed no subtherapeut ic

89 ant ib iot ics but receiving only therapeut ic antibiotics , 2 6 % among isol ates from swine never having received ant ib iotics and in 1 0 0 % of the isolates from swine cont inuously exposed to subtherapeutic levels of antibiotics . Langlois et a1 . 1 1 found less o f a decrease i n ant ib iot ic-res istant col i form organisms in pigs given therapeutic leve l s of ant ib iotics compared to p igs fed cont inuous subtherapeut ic l eve l s of ant ib iot ics once the drugs were withdrawn . There fore , Langl o i s et a1 . 1 1 has suggested therapeut ic doses o f ant ib iotics may have a more marked ef fect than subtherapeut ic doses o f antibiotics . They found bacterial isolates from p igs that rece ived therapeutic doses of one o f the tetracycl ines for only 14 days ( total of 2 2 . 0 �g/ g ) had more ant ibiotic res istance than those that rece ived subtherapeutic doses ( total o f 2 7 . 5 �g/ g ) for 85 days . Variab i l ity in the frequency of ant ibiotic res istance of salmonel l ae isol ated from healthy poultry has been noted . S almons 1 9 a has s umma ri z ed several industry-sponsored studies . I n the survey o f chickens , "by far the predominance o f Salmonella isolates were sensitive to the broad spectrum o f ant ibiot ics used in human o r animal therapy . However , isolates from turkeys were 2 2 -2 3 % res istant to streptomyc ins , tetracycl ine , panamycin and neomyc in . " Other reports have found s imilar variations between the preval ence o f res istance among species , by years and by geographical l ocations . 2 , 3 , 1 3 , 14 , 1 6 , 1 9 They were unable to correl ate level of antimicrobial drug use and percentage o f res istance in most o f these studies ; percentage of res istance was reported for tetracycl ine as 5 0 % to 8 5% and for amp ic il l in as 1 6 % to 8 0 % wh ich agrees with the results submitted to the committee . Two labs also reported a decreased percentage of res istant organisms . 1 � , 1 6 I n conclus ion , there have been several reports and surveys of res i stance of various enterobacteri aceae to various ant ib iotics in cattle , swine , and poultry within the United States . These reports general ly agree that feeding subtherapeutic antib iotics to anima l s or therapeut ical ly treating anima l s with various antib iotics causes an increa sed in the frequency o f isolation o f Salmonella spp . and � QQl! that are res istant to those antibiotics . However , there appears to be a regional and temporal d i f ference in the percentage of res istance and some variation of res i stance expressed between animal spec ies . These results probably reflect the d i f ference of usage both subtherapeut ica l ly and therapeut ica l l y of the various ant ib iotics between poultry , cattle , and swine spec imens submitted to these l abs . Vary ing production methods , stress , and management pract ices could a l so explain some of the d i f ferences and reported decreases in res istance . Al so , these data indicate that the percentage of res istance to ant imicrob ial agents in isolates o f salmone l l a e

90 from anima l s i n the u . s . i s 3 to 5 t imes greater than that in isolates from humans . Greater d i f ferences are seen in the data for isolates of � £Qli in humans or anima l s , i f we assume that hospital i zed patients or range cattle represent a sma l l port ion of the total human or animal popul at ions , respect ively . S ince farm animals outnumber humans in the u . s . ( see Chapter IV ) , they harbor in their intest ina l fl ora a reservo ir of res istance genes that may be an order o f magnitude l arger than that of the fl ora i n the total human popul at ion . EFFECT OF BANNING THE USE OF SUQTHEBAPEUTIC DOSES OF ANTIBIOTICS To assess the impact of subtherapeut ic use of antibiotics on the sel ect ion of antimicrob ial -re s i stant bacteria isol ated from animals that may also cause human d i sease , it i s critical to review the experience in England and the other countries where growth promot ing use o f ant ib iotics has been proh ibited . In 1 9 6 9 , Swann e t al . 2 4 were appo inted to the Jo int Committee on the Use o f Ant ib iotics i n Animal Husbandry and Veterinary Med ic ine in Engl and to obta in in format ion about an increase in res i stant stra ins ; it produced a report that attempted to explain in s imple and stra ight forward terms how the use of ant ibiotics in animals may a ffect both humans and anima l s . Other concerns that influenced the Swann committee included the presence of trace amounts of ant ib iotics in meat or poultry products consumed by humans and the ir potent ial for causing a l l ergic or toxic react ions and a l l owing the sel ect ion of res istant bacteria from among the nosocomial flora , and the pos s ib i l ity that � typhi would devel op res i stance to chloramphen icol , the drug of cho ice at that time . Recommendations adopted included the divi s i on of ant ib iot ics for agricultural use into two classes : therapeut ic antibiot i cs , for use in treating bacterial in fect ions in an ima l s and ava i l able only by prescription from a veterinarian ; and " Feed " ant ib iotics used in subtherapeut ic doses for growth promot ion that is ava i l able to the farmer without a prescript ion through feed merchants or farm stores . It was recommended that the latter class be restricted to those drugs that have no use in human medic ine . Thus , Z inc Bac itracin , Virginiamyc in , Avoprac in have been used and apparently do not select stra ins that would be res istant to the tetracycl ines , pen ic i l l in , and other antibiot ics . Penic i l l in and the tetracycl ines have not been used for feed addit ives or growth promotion . Although those two ant ibiotics could be added to animal feed i f the purpose was for treatment or prevent ion of a bacterial in fect ion , ne ither

91 could be included at l ow concentrations for promot ing growth . such use o f an ant ibiotic in feed is prescribed by a veterinarian for a part icular disease episode , general ly for no longer than 4 weeks . The subtherapeutic dose ( 2 0 0 gjton ) o f ant imicrob ials in the United States i s cons idered a therapeutic dose in the United Kingdom . Therefore , it is d i f f icult to compare the impact due to the use of this concentration of ant ib iotics in each of these two countries on the sel ection of res istance because the appl ications for this concentrat ion have been d i f ferent . This d i f ference in appl ication of dosage is critical to our understanding in the United States about the pos ition of the British scient ists who feel that 2 0 0 gjton is a concentrat ion that is important in selecting res istance in in fectious bacterial stra ins . Many changes have occurred in anima l husbandry s ince 1 9 6 9 , and there was no systematic col l ect ion of data be fore that date , so the ef fect of the Swann Committee recommendat ions cannot be accurately assessed . 1 8 , 2 7 , 2 8 Interested investigators and government groups have gathered data on the number and types of some res istant organ isms in an ima l s and humans in the British I s l es , but no comprehens ive prospect ive study has been initiated to evaluate the e f fect of the recommendat ions . Antib iot ic use apparently had increased in both humans and anima l s s ince the Swann report ( see Tab l e 1 in Braude 4 ) . Al so , human use of ant ib iot ics in the United Kingdom increased rapidly ; it was 17 t imes the veterinary use in 1 9 8 0 , but be fore the Swann report , the human use was only 1 . 4 t imes the veterinary use . 3 0 Walton and other researchers have become conv inced that the therapeut ic use of antibiotics in humans , as we l l as in animal s , causes the sel ection of res i stance in the bacter ial stra ins in humans . 18 , 2 5 , 2 7 , 2 8 They contend that concentrat ions of antibiotics achieved in anima l s rece iv ing subtherapeut ic concentrat ions of antibiotics ( presumably less than 2 0 0 gjton of penic i l l in or the tetracycl ines ) did not reach the critical points necessary for the sel ect ion of res istant stra ins . 2 8 Although there is concern that some bacterial stra ins found in animals have multipl e ant ibiotic res i stance that could be a haz ard to human health , the situat ion has not worsened desp ite increas ing ant ib iot ic use in anima l s . Furthermore , it is the general feel ing of some scient i sts in the Un ited Kingdom that the Swann Committee recommendations have had no impact in reducing th is ha zard . The ava i l able data are suffic ient for an assessment o f the changes i n res istance patterns as wel l as assessment of the numbers of isolations of various species of salmonel l ae in Engl and s ince 19 7 0 . Soj ka et al . 2 3 have periodical ly reported s imilar results over the period from 19 7 2 - 1 9 8 6 . Those surveys clearly indicate that the recommendat ions in the Swann report did not stop the devel opment o f ant ib iotic

92 res istance , especially res istant to penici l l ins and tetracycl ines . Chloramphenicol res istance has steadi ly increased in some isolates , despite the prohibition of the use of thi s ant ibiotic in feed . The authors o f those surveys conclude that the therapeutic use of ant ibiotics in an imals , combined with poor animal handling and management pract ices , espec ial ly regarding calves , does cont inue to promote the development of res istant stra ins . 1 8 , 2 5 , 2 7 , 2 8 Res istance of salmone l l ae to penici l l ins and tetracycl ines in anima l s varies with the animal ; those of bovine origin are less l ikely to be sensit ive to e ither kind of drug than those from poultry . In a l l isolates o f res istant � typhimurium , predominately phage type 2 0 4 C , and rel ated types 4 9 and 2 0 4 --accounted for most of the res i stant strains . Those phage types appeared in calves in 1 9 7 9 , spread widely in the next 2 years , and they rema in the predominant types in cattle ( 5 9 % in 1 9 8 5 ) . Phage type 2 0 4 C has a l s o caused enteritis i n humans as observed in 4 % o f the patients in 19 8 5 . The disease has usually cons isted of mild to moderate diarrhea , but several of the 677 pat ients with � typhimurium infection in 1 9 7 7 - 1 9 8 4 had to be hospital i zed for severe diarrhea . The cases in two outbreaks might have been due to consumption of raw mi l k , while most of the other cases were thought to be farm workers , but that has not been con f i rmed . Most people with infections had no farming connections . The bacterial stra ins isol ated from these cases were res istant to ampicil l in , chloramphen icol , gentamicin , tetracycl ine , and trimethoprim . Stra in o f 2 0 4 C phage type accounts for 7 7 % o f al l the Salmonella stra ins isolated from calves in 1 9 8 5 . 9 Apparently , in fected calves stop shedding � typhimurium before they reach slaughter weight and , there fore do not serve as a source of infect ion to humans because they do not enter the food cha in in great numbers . The spread of phage type 2 04 C probably occurred because o f the pract ice o f sel l ing colost rum -deprived ca lves from broker to broker several t imes during the first 56 days of l i fe . Calves apparently are susceptible to Salmonella infect ion during this early period and poor management pract ices contribute to the problem during frequent trips to market , whereby they acquire salmonel lae from other anima l s . It is speculated that the res istant salmone l l ae became res i stant because of futile attempts to treat cal f scours with numerous antib iotics . 2 5 These salmonel lae a l so appear to have a predi l ection for acquiring plasmids . Each year s ince isol ation the res istance pattern of phage type 2 0 4 C has broadened ; gentamicin is the most recent ant ib iotic to wh ich the stra in has developed res i stance . 2 3 The pl asmid that codes for res istance to gentamicin also con fers res istance to net i lmic in , tobramyc in , and apramycin . The l ast named is an aminoglycos ide that is used to treat sa lmonel l a in fect ions in calves , its use is probably the reason that res istance to

93 apramycin and qentamicin appeared . Phaqe type 2 0 4 C has a l so appeared in the Netherlands2 6 and Denmark , 8 and was imported into the European countries via veal calves . The appearance amonq bacterial isol ates o f � typhimurium phaqe type 2 04 C with multiple antib iotic res i stance has been an isolated event in Enql and . Other S almonella spec ies have not shown the same rapid increase in acquirinq res istance . There have been dramatic shi fts in the number of i solat ions of various other res istant Salmonella spec ies . For example , � agona appeared in the early 1 9 7 0 s in Enql and and the United States , hav inq been imported from Peru with contaminated f ish meal ( to be used as poultry feed ) . 9 By 1 9 7 5 , there were 1 , 8 2 1 human isolates , the peak number . The number fel l to around 4 5 0 for the years 1 9 7 9 - 1 9 8 3 : reasons for the decl ine are unknown . � hadar appeared in 1 9 7 1 and peaked in 1 9 7 9 at 2 , 4 8 0 isolates . Thi s stra in was isol ated from turkey breedinq stock , and the meat from contaminated , undercooked larqe birds caused outbreaks . 9 In 1 9 8 4 , only 4 9 6 isolations were reported : aqa in , the reasons for the decl ine are unknown . Those two examples demonstrate that the presence of antibiotics in anima l s did not cause the stra ins to prol i ferate or to develop res istance to ant ibiotics , such as occurred with � typhimurium phaqe type 2 0 4 C and rel ated types . Walton noted several lessons that were learned from the Un ited Kinqdom ' s eXPerience with the Swann Committee recommendat ions . 2 7 , 2 8 Ant ibiot ics , such as the tetracycl ines and penic i l l in used in the product ion of meat products , did not become ine f fect ive , desp ite the development of res istance by bacteria . Those two cl asses of druqs cont inue to be used and to be e f fective prophylactica l ly and therapeut ica l ly . Food anima l s have short l i fe spans--bro i ler ch ickens , 3 5 - 5 6 days : p iqs , 3 . 5 t o 5 months : and cattle 2 . 5 years--and the rapid turnover results in the destruct ion of larqe numbers of bacteria . 2 7 , 2 8 When larqe batches of animals leave the ir quarters , cl eaninq is carried out with hiqh-pressure water , which not only removes most qross amounts of o f fal but also d i lutes and kil l s bacteria . Better control o f ant ib iot ics has been inst ituted because of the requi rement that veterinarians write prescriptions for the use of ant ibiotics in feed . One item that has not been clear from the discuss i ons presented above is the human health haz ard assoc iated with the increas inq number of sa lmone l l ae isol ated in the United Kinqdom . F iqure V- 1 shows the inc idence of salmonel losis in Enql and and Wales in 1 9 4 1 - 1 9 8 4 . This shows a s iqn i f icant increase in the numbers of inc idents durinq these years . Interpretat ion o f the trends indicates an ep idemic o f � typhimurium in fect ion in the Un ited Kinqdom . Total f igures for mortal ity caused by salmone l l ae is not ava i l able to the committee . However , some f iqures have been obta ined :

94 10000 Number 8000 of incidents !\ I ,·"' £ I I \_,-.'\,. I . . .. : I : � •• 4000 . ., tt I _ ...., A : I .,.. :-·--�\ : ,":: I \: J .I , • '- ' -: , 2000 \ '- I " ,.., , . ...., . --...... --j-._,' ......,.... . . . . .. ... .. ' .,, ". ....,. . ., .·- ... -- �--- ··..· .... -r .. . ... __... .. -""' . 0 • ' • 0 0 I ' . . . . . . . . . . . . . . . . , , . . . . 194 1 1960 B 70 1980 F i gure V- 1 . Sa lmonel losis , Engl and and Wa les , 1 9 4 1 - 19 8 4 . Reprinted from Palmer and Rowe . 17 Total Salmone l l ae Sa lmone l l a typh imurium Other salmonel l a serotypes

95 a maj or hospital outbreak i n 19 8 4 involved about 3 5 0 patients and 5 0 sta f f members ; 19 patients died . � typhimurium was the causat ive organ ism . Other less striking examples o f the deaths during outbreaks l isted were as fol l ows : 2 o f 6 5 4 patients infected by � typbumurium from raw milk in 19 8 1 ; none of 5 0 0 patients in fected by � montevideo from chicken in 19 8 1 ; none o f 2 4 5 patients infected by � napoli from chocolate in 1 9 8 2 ; 2 of 7 6 6 patients infected by � enterit idis from a sp icy glaze in 1 9 8 4 : 4 o f 2 7 4 patients infected by � yirchow from cooked meats in 19 8 5 : and 1 of 60 pat ients in fected by � eal inq from infant dried milk in 19 8 5 . Those are selected outbreaks and do not represent a thorough survey . The res istance of these bacteria to various antimicrob ial drugs was not reported . No great increase in mortal ity occurred inasmuch as the authors who reported on the incidence of the di sease and the apparent increase in numbers of bacterial i solates did not indicate any increase in mortal ity . 1 8 , 2 5 , 2 7 , 2 8 Wa lton 2 7 , 2 8 a l so suggested in 1 9 8 5 that the 1 5 years of ant ibiotic controls in the United Kingdom as recommended by the Swann Committee and s imilar control s in Europe had provided gu idance for other countries that wanted to devel op ant ib iotic control pol ic ies . Other authors such as Rowe and Threl fal l 1 8 appeared to concur , with the fo l l owing suggest ion : Total control of ant ib iot ic use is neither poss ib l e nor even necessary . Rather a redef inition o f the current pol icy is needed , plus updated pract ical measures to assess the most e ffect ive use of the drugs . In summa ry , the United Kingdom ' s experience with restrict ing the use o f antibiotics in feeds has shown that res istance in bacteria probably develop in spite of the contro l s on " feed " ( subtherapeutic concentrat ions ) ant ib iotics not used in humans . Thus , prohibition of subtherapeut ic doses of antibiotics in anima l s has not prevented or even a f fected the preval ence of res istant bacteria in the United Kingdom . In conclus ion , it is impossible to ascerta in the e f fectiveness of the Swann Committee recommendat ions , because agricultural practices have changed substantially and because the therapeut ic use of antibiotics-- is a more important stress in the select ion of res istant organisms than subtherapeut ic . Res istant stra ins of salmonel l ae and other bacteria have pers isted ; some have increased in inc idence , and others have decreased . The reasons for the changes are unknown , but do not appear to be rel ated solely to the presence of antibiotics in the gastro intestinal tract . Human health ha z ards persist , perhaps they have increased . Human cases of salmonellosis have increased , but whether mortal ity from thi s d isease has changed cannot be ascertained .

96 BEFEBENCES 1. Atkinson , B . A . , and v . Lorian . Ant imicrob ial agent susceptibil ity patterns of bacteria in hosp ita l s from 1 9 7 1 - 1 9 8 2 . J . Cl in . Microb iol . 2 0 : 7 9 1 -7 9 6 , 1 9 8 4 . 2. Bissett , M . I . , s . L . Abbott , and R . M . Wood . Antimicrobial res istance and R factors in salmonel lae isolated in Cal i fornia ( 19 7 1 - 1 9 7 2 ) . Antimicrob . Agents Chemother . 5 : 1 6 1- 1 6 8 , 1 9 7 4 . 3. Blackburn , B . o . , L . K . Schalter , and M . R . Swanson . Ant ibiotic res istance of members o f the genus salmonel lae isolated from chickens , turkeys , cattle , and swine in the United states during October 1 9 8 1 through September 1 9 8 2 . Amer . J . Vet . Res . 4 5 : 1 2 4 5 - 1 1 4 9 , 1 9 8 4 . 4. Braude , R . Antibiotics in animal feeds in Great Britain . J . Anim . Sci . 4 6 : 1 4 2 5 , 1 9 7 8 . 5. Cherub in , c . E . , M . S zmuness , and J . Winter . Ant ibiotic res istance of salmonel lae . Northeastern Un ited S tates-- 197 0 . N . Y . State J . Med . 7 2 : 3 6 9 - 3 7 2 , 1 9 7 2 . 6. Fagerberg , D . J . Sa lmonella inc idence and antimicrob ial res istance in fecal and feed samples of product ion bro i l ers , bee f cattle and swine at s laughter pl ants in the Un ited States--A four year study . Soc iety o f An imal Science , 19 8 5 . 7. Gusta fson , R . H . , J . D . Kobland , and P . H . Langner . Inc idence and Antibiotic Res istance o f Sa lmone l l a in Market Swine . Proc . I PVS congress , June 2 2 -2 4 , 1 9 7 6 . 8. Jorgensen , s . T . Prevalence and molecular epidemiology o f ant ib iot ic-resistant � typhimurium and � dublin in Dan i sh cattl e . Acta Path . Microbic! . Immunol . Scand . 9 1 ( Sec . B ) : 1 6 3 - 1 6 8 , 19 8 3 . 9. Kirby , D . and c . Wray . Salmone l l a Spec ia l . Veterinary aspects and prospects for control . PHLS Microbiol . Digest 3 : 1 2 - 1 3 , 1 9 8 6 . 10 . Langl o i s , B . E . , K . A . Dawson , G . L . Cromwe l l , and T . s . Stahly . Ant ibiotic res istance in pigs fo l l owing a 1 3 year ban . J . An im . Sci . 6 2 ( Suppl . 3 ) : 18 - 3 2 , 1 9 8 6 . 11 . Langlois , B . E . , K . A . Dawson , G . L . Cromwe l l , and T . s. Stahly . Antibiotic res istance of feca l co l i forms from swine fed subtherapeut ic and therapeut ic leve l s o f chl ortetracycl ine . J . An im . Sci . 5 8 : 6 6 6 - 6 7 4 , 1 9 8 4 .

97 12 . Lester , s . c . , et al . Antib iot ic res istance in Esqberichia 2211 of hea lthy children in the U . S . A . , Venezuela , and China . Twenty-Seventh Interscience Conference on Antimicrobial Aqents and Chemotherapy , ASM , p . 2 7 6 , Oct . , 1 9 8 7 . 13 . Lorian , v . Salmonel lae susceptibi l ity patterns in hospita ls from 1 9 7 5 throuqh 1 9 8 4 . J . Cl in . Microbial . 2 3 : 8 2 6 -8 2 7 , 1 9 6 8 . 14 . MacDonald , K . L . , M . L . Cohen , N . T . Harqrett-Bean , J . G . Wel l s , N . D . Puhr , s . F . Col l in , and P . A . Blake . Chanqes in antimicrob ial res istance of Salmonel l ae isolated from humans in the United States . J . Amer . Med . Assoc . 2 58 : 1 4 9 6-14 9 9 , 1 9 8 7 . 15 . O ' Brien , T . F . , J . D . Hopkins , E . s . Gil leece , A . A . Mede iros , R . L . Kent , B . o . Blackburn , M . Holmes , J . P . Reardon , J . M . Verqeront , w . L . Sche l l , E . Christenson , M . L . Bissett , and E . v . Morse . Molecular ep idemioloqy of ant ib iot ic res istance in salmonel lae from anima l s and human be inqs in the United States . N . Enql . J . Med . 3 07 : 1 - 6 , 1 9 8 2 . 16 . O ' Brien , T . F . , and Members of Task Force 2 . Res istance of bacteria to antibacterial aqents : Report of Task Force 2 . Rev . Inf . Dis . 9 : S 2 4 4 -S2 6 0 , 1 9 8 7 . 17 . Palmer , s . R . , and R . Rowe . Trends in salmone l l a infections . PHLS Microbial . Diqest 3 ( 2 ) : 2 , 1 9 8 6 . 18 . Rowe , B . and E . J . Threl fa l l . Antibiotic res istance in Salmonel la . PHLS Microbial . Diqest 3 : 6 -7 , 1 9 8 6 . 19 . Saad , A . F . , and w . E . Farrar . Ant imicrobial res istance and R factors in salmonellae isolated from humans and animals in Georqia and South Carol ina . South . Med . J . 7 0 : 3 05-308 , 1977 . 1 9 a . Salomons , I . A . Antibiotics in animal feeds--human and animal sa fety issues . J . Anim . Sci . 4 6 : 1 3 6 0- 1 3 6 8 , 1968 . 20. Schroeder , s . A . , P . M . Terry , and J . v . Bennett . Antibiotic res istance and trans fer factor in salmonella in the United States-- 1 9 6 7 . J . Amer . Med . Assoc . 2 0 5 : 9 0 3 -9 0 6 , 1 9 6 8 .

98 21 . S iegal , D . , w . G . Huber , and F . Enloe . Continuous non­ therapeutic use of antibacterial drugs in feed and drug res istance of the gram-negative enteric florae of food­ producing animals . Ant imicrob . Agents Chemother . 6 : 6 9 7 -7 0 1 , 1 9 7 4 . 22 . Spogaard , H . Incidence of drug res istance and transmiss ible R factors in strains of � £Qli isolated from faeces of healthy pigs . Acta Vet . Scand . 14 : 3 8 1- 3 9 1 , 19 7 3 . 23 . Soj ka , w . J . , c . Wray , and I . McLaren . A survey of drug res istance in salmonellae isolated from anima l s in England and Wales in 1 9 8 2 and 1 9 8 3 . Brit . Vet . J . , 1 4 2 : 3 17 - 3 8 0 , 1 9 8 6 . 24 . Swann , M . M . et al . Joint Committee on the Use o f Antibiotics In Animal Husbandry and Veterinary Medicine . London , England : Her Maj esty ' s Stationery Office , 1 9 6 9 . 25 . Threl fal l , E . J . , B . Rowe , J . L . Ferguson , and L . R . Ward . Increasing incidence o f res istance to gentamicin and related aminoglycos ides in Salmonella typhimurium phage type 2 04 C in England , Wales and Scotland . Vet . Rec . 1 1 7 ( 14 ) 3 55-3 57 , 19 8 5 . 26 . vanLeeuwen , w . J . , J . vanEmbden , P . Guinee , E . H . Kampelmacher , A . Manten , M . vanSchothorst , and c . E . Voodg . Decrease in drug resistance in salmonella in the Netherlands . Antimicrob . Agents Chemother . 1 6 : 2 3 7 -2 3 9 , 1979 . 27 . Walton , J . R . Antibiotic res istance : An overview . Vet . Rec . 1 2 2 ( 1 1 ) : 2 4 9 -2 5 1 , 1 9 8 8 . 28 . Wal ton , J . R . Impact o f antibiotic restriction in animal productions on public health . J . Anim . Sci . 6 2 ( Suppl 3 ) : 7 4 -8 5 , 19 8 5 . 29 . Winshe l l , E . B . , c . Cherubin , J . Winter , and H . c . Neu . Antibiotic resistance in salmonella in the eastern United States . Antimicrob . Agents Chemother . 9 : 8 6 -89 , 1969 . 30. Yeoman , G . H . 1 9 8 2 veterinary practice and antibiotics in the control o f antibiotic res istant bacteria . In c . H . Stuart-Harris , Ed . The Beecham Col loquia . London , England : Academic Press , 1 9 8 2 .

VI EVI DENCE OF TRANSMISS ION OF PATHOGENS OF FARM ORIGIN TO HUMANS Evidence of transmiss ion of bacteria from farm-anima l ­ origin t o humans has been found in two genera o f bacteria : Escherichia and Salmonel la . ESCHERICHIA QQLI Escherichia . col i and other enteric bacteria res istant to multiple drugs have been found to spread from farm anima l s into farm workers , the i r fami l ies , and the nearby community has been investigated . Such studies have , in genera l , indicated that mul t iple-drug-resi stant E· QQli organisms do indeed colon i z e farm workers , and to a l esser extent the i r fami l ies , and a t times even spreads t o nearby non- farm populat ions . No evidence has suggested , however , that mul tiple-drug-res istant � - QQli of farm origin is associated with a higher risk of ser ious infection than � - QQli of non­ farm origin . Perhaps the f i rst systemic study o f the change o f col i form organi sms from susceptible t o multipl e-drug­ res istant in farm animal s and in eleven members of the family on this farm . Th is was a prospect ive study carried out by Levy and Assoc iates . l l The systemic fecal sampl ing showed an increase in res istant � col i within a week a fter start o f the feed ing of tetracycl ine-suppl emented feed t o a fl ock of chickens . The numbers o f tetracycl ine-res istant intestinal col i forms a l so increased in the eleven members of this farm fami ly , but not in the ir ne ighbors . Within 3 - 5 months a fter medicating the ch ickens , 3 1 % of the fecal samples taken each week from each member of the farm family yielded bacterial populations o f which 8 0 % o f the col i form bacteria col onies were tetracycl ine-res istant , compared with 6 . 8 % of the sampl es from neighbors . About 6 months a fter the tetracyc l ines had been removed from the animal feed , the percentage of res istance organisms in farm dwel l ers ' fecal samp l es that yielded col i form organisms over 8 0 % o f wh ich were tetracycl ine-resistant had decreased to approximately the magnitude found be fore use o f the tetracycl ines was started . The rap idity with which commercially processed poul try i s marketed precludes a study over a l ong time period of the change in the percentage o f tetracycl ine-resi stant 99

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